Conventionally, a Non-Steroidal Anti-Inflammatory Drug (hereinafter, referred to as “NSAID”) is known as an anti-inflammatory analgesic. This NSAID has an action of suppressing production of prostaglandin correlated with inflammation and pain, by inhibiting cyclooxygenase (hereinafter, referred to as “COX”) catalyzing an initial step in an arachidonate cascade which is a metabolic route intensifying pain.
However, since prostaglandin has various actions in addition to actions such as inflammation and pain, serious side effects may occur in some cases in case that production of prostaglandin is suppressed to an extent more than necessary by administration of NSAID. For example, when the action of COX is suppressed, the activity of lipoxygenase is enhanced to increase leukotriene. As the result, secretion of gastric juice decreases, and simultaneously active oxygen disrupting a mucous membrane of a digestive tract increases, leading to the development of an ulcer. Additionally, side effects such as kidney function impairment, liver function impairment, skin eruption are known, and aspirin asthma may be induced particularly as a life-threatening side effect.
Accordingly, regarding NSAID, external preparations with a relatively low risk of these side effects have been developed. That is, such an external preparation delivers NSAID transdermally to an affected area so that systemic side effects can be reduced and the drug concentration can be enhanced in a local affected area.
However, some NSAIDs are extremely poor in skin permeability and their effects remarkably decrease in case that they are administered as external preparations compared with the case of oral administration. Then, technologies for improving skin permeability of NSAIDs are developed variously.
For example, an invention described in Kokai Publication No. Hei 14-128699 is an anti-inflammatory analgesic preparation for external use containing an NSAID and a local anesthetic, and has an object to be solved of improving skin permeability. In an example of this publication, a preparation containing loxoprofen sodium as an NSAID and a local anesthetic is prepared, and a test for evaluating its skin permeability is described.
However, evaluation of only skin permeability is not satisfactory for determining a value of a drug delivery system of an NSAID. The reason for this is that a portion generating pain is muscle tissue and joint tissue, and a portion to which an NSAID should reach is not a skin surface portion at which capillary blood vessels are present, but is a deeper portion at which muscle tissues and the like are present. Namely, when skin permeability and blood concentration are especially improved, the drug may not necessarily have an effect of penetratability and diffusivity in muscle tissues or the like and may not act directly on an affected area. Actually, according to findings of the present inventors, penetratability and diffusivity of some kind of NSAID in tissues are deteriorated by adding a local anesthetic. Nonetheless, in conventional preparation design, penetratability and diffusivity into portions deeper than corium are not taken into consideration at all under present circumstances.
Further, even with a preparation showing high skin permeability, unless it allows an NSAID to penetrate and diffuse into a deeper portion, the drug cannot but remain on a surface portion of the skin. As the result, secondary disorders such as decrease in safety due to skin irritation and the like are possibly caused. Additionally, it is thought that when the concentration of an NSAID inside the skin increases, concentration gradient against the drug present on the surface of the skin decreases, and therefore its absorption efficiency is deteriorated. Consequently, even if the content of an NSAID in an external preparation is increased, the amount to be absorbed does not increase and its effect is neither improved, thus, the NSAID concentration in traditional external preparations is at most about 1%, and its effect is recognized to be saturated even if it is further added.
Other preparations containing an NSAID and a local anesthetic are also known, like the invention described in Kokai Publication No. Hei 14-128699. For example, WO 01/047559 describes a patch drug for external use containing a local anesthetic and an NSAID, from the point of view of letting it act on both the inflammatory portion and the peripheral nervous system, and indomethacin and the like are exemplified as specific examples of NSAID. However, there is no description regarding etodolac nor skin permeability and the like, although this publication discloses the result of a sensory evaluation test as an example.
Also WO 03/099293 describes salts formed with an NSAID having a carboxyl group and a local anesthetic having an amino group, and describes etodolac as an example of NSAID. However, the technology described in this publication is directed to enhancing drug-sustained-releasability of an injection and the like by decreasing water-solubility of NSAID, but is not directed to external use. Thus, there are neither descriptions nor suggestions at all regarding skin permeability, nor penetratability nor diffusivity in muscle tissues and the like. Actually, produced salts in examples of this publication are only those containing diphnysal as an NSAID.
By the way, there are mainly type 1 and type 2 isozymes of COX. COX-1 is expressed constitutively in most tissues of the body, and is thought to fill the role of maintaining stability of the body including a stomach mucous membrane protecting action and the like. On the other hand, though the expression level of COX-2 under usual conditions is low, it is induced by inflammatory irritation and the like. Thus, it is thought that when COX-2 can be inhibited selectively, inflammation and the like can be reduced while suppressing the body damage. However, NSAIDs such as indomethacin, dichlofenac and the like, disclosed specifically as examples in the prior publications described above, inhibit COX non-selectively. That is, even if skin permeability of these external preparations is enhanced, side effects accompanying the increase of drug concentration in plasma can cause a problem, rendering the external preparations meaningless.